The present invention relates to methods and compositions for the prevention and treatment of cardiovascular disease, specifically, but not limited to, restenosis and arterial inflammation with the administration of non-steroidal anti-inflammatory drugs (NSAIDs). The present invention relates to methods and compositions for preventing and/or treating restenosis in mammals, by inducing or stimulating apoptosis, reducing proliferation, inducing quiescence, inhibiting cell migration, altering argiogenesis, altering extracellular matrix formation, or influencing cell differentiation of the cells of the vessel wall that contribute to arterial lesions. In particular, the methods and compositions of the invention are useful in the stimulation of cell death and/or the inhibition of the robust response to arterial injury by inhibition of the proliferation or migration of vascular cells or other target cells that contribute to arterial lesions formation.
Cardiovascular disease, including, but not limited to, atheroslerosis, ischemia, reperfusion, hypertension, restenosis and arterial inflammation, is a major health risk, throughout the industrialized world. Atherosclerosis, the most prevalent of cardiovascular diseases, is the principal cause of heart attack, stroke, gangrene, clandication, and gangrene of the extremities. It is a complex disease involving many cell types and molecular factors. Ross, 1993, Nature 362:801-809. Under normal circumstances, a protective response is mounted when there is injury to the endothelium and smooth muscle cells of the wall of the artery, and consists of formation of fatty and fibrous lesions or plaques, accompanied by inflammation. The advanced lesions of atherosclerosis may occlude the artery affected, and result from an excessive inflammatory response to different forms of injury. For example, shear stresses are thought to be responsive for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures.
Ischemia is a condition when there is a lack of oxygen supply in tissues of organs due to inadequate perfusion due to atheroslerotic or restenotic lesions, stroke, or anemia, to name a few. The most common cause of ischemia in the heart is atherosclerotic disease of the epicardial coronary arteries. Myocardial ischemia can also occur if myocardial oxygen demands are abnormally increased, due to hypertension or aortic stenosis.
Since an excessive inflammatoryxe2x80x94fibroproliferative response is implicated in atherosclerosis and ischemia, the expression of certain factors such as growth factors, cytokines and lipids involved in inflammation and cell proliferation, has been investigated. For example, the expression of platelet derived growth factor (PDGF) was studied in rats during repair of arterial injury (Majesky et al., 1990, J. Cell. Biol. III;2149); the expression of insulin-like growth factor-I(IGF-I) was studied after balloon deendothelialization of the at aorta (Corceck et al., 1990, Circulation Research 66:1755-1760); and in bovine aortic endothelial cells subjected to fluid shear stress (Resnick et al., 1993, Proc. Natl. Acad. Sci. USA 90:4591-4595).
The principal surgical approaches to the treatment of acute or chronic ischemic atherosclerosis are percutaneous translumenal angioplasty (PCTA), bypass grafting, and endarterectomy. Revasularization procedures are frequently used as interventions in vascular disease, including in the unstable coronary syndromes. For example, PCTA and related procedures, including stent placement, are performed on over 400,000 patients in the United States alone. Among patients who have undergone initially successful angioplasty, the outcome over the first 6-12 months is influenced primarily by the development of recurrent stenosis or xe2x80x9crestenosisxe2x80x9d at treated sites. The failure rate after these approaches due to restenosis, in which the occlusions recur and often become even worse, is very high (30-50%). It appears that much of the restenosis is due to further inflammation, smooth muscle accumulation and thrombosis or other factors. The incidence of restenosis has essentially remained unchanged since the introduction of angioplastic techniques, and is approximately 30-50%, despite treatment with aspirin and related compounds that inhibit platelet aggregation. In fact, recent figures showed 30% of angioplasty patients require a revascularization procedure within one year of their original procedure due to restenosis, resulting in approximately two billion dollars in health care charges on top of the initial costs for surgery.
Other studies have focused on the expression of genes and gene products presumed to be involved in the processes leading to restenosis and inflammatory proliferative reactions. However, such approaches cannot identify the full range of gene products that are involved in the disease process; and much less identify those which may serve as therapeutic targets for prevention and treatment of restenosis and inflammatory proliferative diseases.
In accordance with the invention, methods and compositions are provided for the prevention and treatment of restenosis by administering non-steroidal anti-inflammatory drugs. The compositions include NSAIDs alone or in combination with lipid lowering agents or diets or antioxidants or angioplastic procedures or other surgical manipulations. The preventive and/or treatment methods can involve inducing apoptosis, reducing proliferation, inducing quiescence, inhibiting macrophage migration, or influencing cell differentiation, and/or clearance of lipoproteins to thereby prevent and/or treat arterial lesions and provide a variety of health benefits.
The present invention can provide a method of preventing)arterial lesions and restenosis by applying NSAIDs which induce apoptosis, reduce proliferation, induce quiescence, inhibit macrophage and smooth muscle cell migration, or influence cell differentiation in the vessel wall. The method can include subjecting the vascular cells to an effective amount of NSAIDs to trigger and induce programmed cell death, reduce proliferation, induce quiescence, inhibit macrophage and smooth muscle cell migration, or influence cell differentiation and prevent occlusive or thrombotic events in arteries or veins.
The present invention can also provide a therapeutic method for the treatment of arterial lesions and restenosis, associated with apoptosis, proliferation, monocyte/macrophage and smooth muscle cell migration, or differentiation of vascular cells by administering an effective amount of an NSAID to induce apoptosis, reduce proliferation, induce quiescence, inhibit macrophage and smooth muscle cell migration, or influence cell differentiation of cells that contribute to atherosclerosis. In accordance with the invention, an effective amount of one or more NSAID is administered to prevent and/or treat a variety of atherosclerotic conditions.
According to an additional aspect of the present invention, there is provided a method to induce apoptosis, reduce proliferation, induce quiescence, inhibit macrophage and smooth muscle cell migration, or influence cell differentiation of cells that contribute to a complex or unstable plaque in restenosis by administering NSAIDs along with an antithrombotic therapy, including the administration of an effective amount of an antithrombotic agent such as heparin or warfarin.
According to yet another, aspect of the present invention, there is provided a method to induce apoptosis, reduce proliferation, induce quiescence, inhibit macrophage and smooth muscle cell migration, or influence cell differentiation of cells that contribute to restenosis by administering NSAIDs along with antioxidant therapy, including the administration of an effective amount of an antioxidant such as vitamin A, vitamin E, N-acetylcysteine, glutathione, vitamin C, and/or magnesium gluconate.
According to yet another aspect of the present invention, there is provided a method to induce apoptosis of cells that contribute to atherosclerosis including the application of NSAIDs in combination with a conventional therapeutic regimen including by-pass surgery, angioplasty, beta-blocker therapy, calcium channel antagonists, magnesium, thrombolytic therapy, antithrombotic therapy or drug therapy.
In accordance with the invention, compositions for the induction of apoptosis, reduction of proliferation, induction of quiescence, inhibition of macrophage and smooth muscle cell migration, or influence on cell differentiation in cells that contribute to restenosis are also provided and include NSAIDS used alone or in combination with conventional therapeutic regimens used to prevent and/or treat arterial or venous lesions or restenosis.
The present invention is based on the (unexpected discovery that NSAIDs are effective in inducing apoptosis, reducing proliferation, inhibiting migration, or influencing differentiation of cells that contribute to restenosis.
It is the object of the present invention to provide compositions and/or methods for inducing apoptosis, reducing proliferation, inhibiting migration, or influencing differentiation of cells that contribute to restenosis.
It is the object of the present invention to provide compositions and/or methods for inducing cell quiescence, reducing proliferation, inhibiting migration, or influencing differentiation in the cells of the vessel wall that contribute to arterial lesions and restenosis.
It is the object of the present invention to provide compositions and/or therapeutic methods for preventing recurrence of atherosclerosis after procedures designed to increase coronary artery blood flow, such as by-pass surgery, reperfusion or angioplasty.
It is also an object of the present invention to provide compositions and/or methods for inducing apoptosis and cell quiescence in cells of the vessel wall using NSAIDs alone or in combination with an effective amount of one or more conventional therapies or antioxidants.
Still other objects and advantages of the invention will in part be obvious and will in part be apparent from the specification and working examples described herein.